Separating the direct effects of traits on atherosclerotic cardiovascular disease from those mediated by type 2 diabetes

Venexia M Walker*, Marijana Vujkovic, Alice R Carter, Neil M Davies, Miriam Udler, Michael Levin, George Davey Smith, Benjamin F Voight, Tom R Gaunt, Scott M Damrauer

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

9 Citations (Scopus)
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Type 2 diabetes and atherosclerotic CVD share many risk factors. This study aimed to systematically assess a broad range of continuous traits to separate their direct effects on coronary and peripheral artery disease from those mediated by type 2 diabetes.

Our main analysis was a two-step Mendelian randomisation for mediation to quantify the extent to which the associations observed between continuous traits and liability to atherosclerotic CVD were mediated by liability to type 2 diabetes. To support this analysis, we performed several univariate Mendelian randomisation analyses to examine the associations between our continuous traits, liability to type 2 diabetes and liability to atherosclerotic CVD.

Eight traits were eligible for the two-step Mendelian randomisation with liability to coronary artery disease as the outcome and we found similar direct and total effects in most cases. Exceptions included fasting insulin and hip circumference where the proportion mediated by liability to type 2 diabetes was estimated as 56% and 52%, respectively. Six traits were eligible for the analysis with liability to peripheral artery disease as the outcome. Again, we found limited evidence to support mediation by liability to type 2 diabetes for all traits apart from fasting insulin (proportion mediated: 70%).

Most traits were found to affect liability to atherosclerotic CVD independently of their relationship with liability to type 2 diabetes. These traits are therefore important for understanding atherosclerotic CVD risk regardless of an individual’s liability to type 2 diabetes.
Original languageEnglish
Pages (from-to)790-799
Number of pages10
Issue number5
Publication statusPublished - 7 Feb 2022

Bibliographical note

Funding Information:
This research was supported by the U.S. Department of Veterans Affairs (IK2-CX001780 to SMD). This publication does not represent the views of the Department of Veterans Affairs or the United States Government. VMW, ARC, NMD, GDS and TRG are members of the Medical Research Council Integrative Epidemiology Unit, which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/6). VMW is also supported by the COVID-19 Longitudinal Health and Wellbeing National Core Study, which is funded by the Medical Research Council (MC_PC_20059). ARC is also supported by the University of Bristol British Heart Foundation Accelerator Award (AA/18/7/34219). NMD is also supported by a Norwegian Research Council (grant no. 295989). MSU is supported by NIDDK K23DK114551. MGL is supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania and the NIH/NHLBI National Research Service Award postdoctoral fellowship (T32HL007843). BFV is supported by the NIH/NIDDK (DK126194 and DK101478).

Funding Information:
Quality control filtering of the UK Biobank data was conducted by R. Mitchell, G. Hemani, T. Dudding, Corbin, S. Harrison and L. Paternoster (Bristol Medical School, University of Bristol) as described in the published protocol []. The MRC IEU UK Biobank GWAS pipeline was developed by B. Elsworth, R. Mitchell, C. Raistrick, L. Paternoster, G. Hemani and T. Gaunt (Bristol Medical School, University of Bristol) []. The authors thank Million Veteran Program (MVP) staff, researchers, and volunteers, who have contributed to MVP, and especially participants who previously served their country in the military and now generously agreed to enrol in the study (see for more details). The citation for MVP is []. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by the Veterans Administration (VA) Cooperative Studies Program (CSP) award #no. G002.

Publisher Copyright:
© 2022, The Author(s).


  • Atherosclerotic cardiovascular disease
  • Coronary artery disease
  • Direct effect
  • Genome-wide association study
  • Indirect effect
  • Mediation
  • Mendelian randomisation
  • Peripheral artery disease
  • Type 2 diabetes


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